Certain 1H-pyrano[3',4',6,7]indolizino[1,2-b]quinolinones are known to have cytotoxic and antiviral activity. Camptothecin {4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin3,14(4H),1 2H)-dione} is an example of one such compound. It is a water-insoluble, cytotoxic alkaloid produced by Camptotheca accuminata plants indigenous to China and Nothapodytes foetida plants indigenous to India. Camptothecin and a few close congeners thereof are the only class of compounds known to inhibit eukaryotic topoisomerase I. Camptothecin (and its known congeners) have no effect on topoisomerase II and none of the known topoisomerase II inhibitors has any significant effect on topoisomerase I.
Certain modifications to the camptothecin molecule have produced compounds which have antiviral activity, but are not cytotoxic or have little cytotoxicity. One of these modifications is that of opening the E ring in camptothecin in a way which gives a 8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one. These compounds and analogs have useful antiviral activity. Such compounds are disclosed in co-pending application Ser. No. 07/589,643, of Patrick L. Burk et al., filed on even date herewith.
This invention provides a method for making certain 8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones. These ketones can be used for preparing other antiviral agents where the indolizino or quinolino portions of these compounds are substituted.